The importance of ventral midbrain (VM) dopamine (DA) synaptic activity is clear from their roles in motor, learning and behavioral disorders, including drug dependence. These synapses contribute to the normal execution of motor sequences, learning, and habit formation learning by mediating short- and long-terhi plasticity at two levels in the basal ganglia, at axon terminals in the striatum, and from somatodendritic areas Together, those actions determine which medium spiny neurons (MSN) synapses transfer activity to substantia nigra reticulara (SNr) nigrothalamic neurons that integrate basal ganglia circuitry and drive the cortex to control behavior, DA released by synaptic vesicle exocytosis from axon terminals acts at multiple pre- and postsynaptic sites that together alter striatonigral dii-ecf and striatopallidal indirect MSN activity. Transmission from sonnatodendritic regions is poorly understood, in part because they lack conventional synaptic vesicles but rather presunned neurosecretory organelles that express VMAT2. Somatodendritic DA release also appears to haVe multiple targets that control nigrothalamic activity, but little is known currently about such synapses. Our hypothesis is that somatodendritic DA release enables frequency-dependent selection of synaptic terminals ofthe striatonigral direct pathway. Our |ab has developed opticaltechniques to measure activity at individual synaptic terminals, including, fluorescent false neurotransmitters (FFNs) that characterize DA release and the synaptic vesicle fusion probe FM 1-43 to striatonigral synapses. Our preliminary evidence indicates that somatodendritic DA release selects striatonigral synapses via presynaptic D1 receptors in a frequency-dependent manner, an effect not detectable using classical methods. We will work with the Edwards lab using mutant mice that Should lack somatodendhtic DA release, the Krietzer lab who have developed means to selectively activate DA, striatonigral and pallidonigral pathways, and the von: Zastrow lab, who are exploring means to interfere with Dl signalling on the MSN neurons, including by amphetamine (AMPH), RELEVANCE (See instructions): The role of dopamine neurotransmission in drug dependence is well established, but the precise means by Which it alters synapses leading to this disorder is unclear, particularly in the midbrain where dopamine release is required but is released using different molecular mechanisms than in most of the rest of the central nervous system. We wiN determine how this release occurs and its relevant synaptic effects.